There is an increasing interest in developing a new drug delivery system (DDS) in recent years. This is due to a social requirement for attaining both safety and high biological availability of drug, i.e. to maximize pharmaceutical activity of known drugs as well as to minimize side effects thereof. In the DDS study, a commonly employed pharmaceutical carrier is a nondegradable high molecular weight compound such as silicone rubber, polyethylene or ethylene-vinyl acetate copolymer. These carriers have given a good result in a percutaneous preparation which is administered through the skin or mucosa. However, when these high molecular weight compounds are implanted or injected into the human body, these carriers remain in the body as a foreign material after release of the drug, which causes a certain amount of trouble for the body. On the contrary, if a high molecular weight compound degradable and absorbable in vivo is employed as the carrier, the carrier is gradually hydrolyzed in the living tissue and simultaneously the drug contained therein is gradually released, and hence, surgical treatment is not required to take out the carrier after the treatment.
The high molecular weight compound degradable and absorbable in vivo includes a natural high molecular weight compound, a typical example of which is collagen, and a synthetic high molecular weight compound, a typical example of which is polylactic acid. The polylactic acid is synthesized from lactic acid which is widely distributed in nature. Besides, this polylactic acid is nonenzymatically hydrolized in vivo and finally exhausted as carbon dioxide and water, and hence, it is an interesting high molecular weight compound degradable and adsorbable in vivo. It has been, therefore, studied as a release-controlling carrier for various drugs since the 1970s [Suong-Hyu Hyon, Seiyaku Kojo (Pharmaceutical Factory), Vol. 13, No. 10, p552, 1983].
Among the known studies, a representative one is a process which comprises dissolving a hydrophobic drug such as a hormone drug (e.g. estradiol, and the like) in an organic solvent such as benzene together with the polylactic acid and then removing the solvent by distillation to formulate a film, powder, pellet and the like (Japanese Patent Second Publication No. 17525/1975). There is also known a so-called solvent evaporation drying method which comprises dissolving the polylactic acid and the hydrophobic drug in an organic solvent for dissolving both components, adding a phase-separating agent to the solution to cause emulsification and then removing the solvent by distillation to collect microparticles (Japanese Patent First Publication No. 33414/1980). However, these methods are applicable only to hydrophobic drugs since they employ a hydrophobic organic solvent such as benzene, chloroform, or the like.
On the other hand, for a release-controlled preparation of a water soluble drug by the polylactic acid type high molecular weight compound, the following procedures have been attempted. Japanese Patent First Publication No. 100516/1985 discloses a procedure wherein a three-layer emulsion of W/O/W type is formed and subjected to drying in water to give microcapsules of polylactic acid. However, this procedure has various disadvantages, i.e. a troublesome process for preparation, a requirement of the third component such as gelatin, in addition to the drug and the polylactic acid, difficulty to obtain microspheres in submicron order and a low rate of incorporation of the drug into capsules due to three-layer structure, and occurance of burst induced by damage of the polylactic acid wall of the microsphere due to a thin wall of the microcapsules, which results in an unstable release of the drug.
Japanese Patent First Publication No. 150609/1982 describes in detail a sustained release of a polypeptide stable to an acid wherein hydrophobic polylactic acid and a hydrophilic polypeptide are dissolved in a mixture of dioxane and water. However, since at least one of the polylactic acid and the polypeptide is not completely dissolved in the mixture, the obtained solution is not clear. Further, in order to avoid undesirable ununiformity of the polylactic acid and the polypeptide, a film prepared by a casting method is further subjected to a compression molding with a hot press to formulate into a polypeptide-containing polylactic acid film, sheet, cylinder, or pulverized product thereof. Although glacial acetic acid is employed as a solvent of the polylactic acid, a mixed solution of the polylactic acid and the polypeptide is lyophilized and then subjected to an extrusion molding at a high temperature to formulate in a cylinder shape. Thus, this literature does not teach a formulation of the microsphere having a particle size of from 0.01 .mu.m to 300 .mu.m like in the present invention.
As is clear from the above description, these known inventions provide with DDS systems having some effects, but are disadvantageous in that they cannot prepare microspheres wherein the hydrophilic physiologically active substance and hydrophobic polylactic acid are uniformly mingled in a molecular order, or in that they include a troublesome procedure for preparation.